Recent theories describe drug abuse as a disorder involving not only positive incentive motivation, but as a disorder also charactered by a loss of inhibitory control. In this project, we will use a laboratory animal model to determine the critical neural mechanisms that underlie the association between risk-related traits and drug abuse, questions that cannot be addressed fully using human subjects. Our working hypothesis is that individual differences in the risk-related traits, reward seeking and inhibition, play a role in drug abuse vulnerability and that individual differences in these two behavioral constructs are mediated by dissociable neural systems. While reward seeking and inhibition undoubtedly involve complex and overlapping neural circuits, our current knowledge suggests that reward seeking is subserved by ascending mesocorticolimbic dopamine (DA) systems, whereas inhibition is subserved by frontal cortical regions involving both DA and serotonin (5-HT). Anatomical studies have also revealed that the medial prefrontal cortex (mPFC) is implicated in both reward seeking and inhibition, whereas the orbitofrontal cortex (OFC) is implicated in inhibition. These neural systems will be examined to determine their role in the association of reward seeking and inhibition with drug reward. Rats will be assessedfor individual differences in reward seeking and inhibition using a variety of behavioral tests and then will assessed for amphetamine reward, DA and 5- HT transporter function, and neural activity assessed by in vivo voltammetry and electrophysiological studies. We predict that rats that are high in reward seeking and low in inhibition will be most vulnerable to the rewarding effect of amphetamine and related drugs. Also, we predict that rats that are high in reward seeking and low in inhibition will be most sensitive to nondrug alternative reinforcers that compete with drug reward, which may have important translational implications for the design of effective drug abuse prevention intervention strategies in humans. Finally, we predict that individual differences in reward seeking and inhibition will be associatedwith differences in DA and 5-HT systems within the nucleus accumbens, mPFC and/or OFC. These results, combined with the human behavioral pharmacology and neuroimaging results in Project 2, will provide a more comprehensive understanding the neural systems involved in risk-related traits relevant to the design of tailored anti-drug prevention intervention messages.